RESUMO
In most mammalian cells, the primary cilium is a microtubule-enriched protrusion of the plasma membrane and acts as a key coordinator of signaling pathways during development and tissue homeostasis. The primary cilium is generated from the basal body, and cancerous inhibitor of protein phosphatase 2A (CIP2A), the overexpression of which stabilizes c-MYC to support the malignant growth of tumor cells, is localized in the centrosome. Here, we show that CIP2A overexpression induces primary cilia disassembly through the activation of Aurora A kinase, and CIP2A depletion increases ciliated cells and cilia length in retinal pigment epithelium (RPE1) cells. CIP2A depletion also shifts metabolism toward the glycolytic pathway by altering the expression of metabolic genes related to glycolysis. However, glycolytic activation in CIP2A-depleted cells does not depend on cilia assembly, even though enhanced cilia assembly alone activates glycolytic metabolism. Collectively, these data suggest that CIP2A promotes primary cilia disassembly and that CIP2A depletion induces metabolic reprogramming independent of primary cilia.
Assuntos
Autoantígenos/metabolismo , Cílios/patologia , Glicólise , Proteínas de Membrana/metabolismo , Proteínas Oncogênicas/metabolismo , Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Autoantígenos/genética , Proliferação de Células , Células Epiteliais/citologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/genética , Neoplasias/genética , Proteínas Oncogênicas/genética , Epitélio Pigmentado da Retina/citologia , Transdução de SinaisRESUMO
Hypoxia-induced interleukin-32ß (IL-32ß) shifts the metabolic program to the enhanced glycolytic pathway. In the present study, the underlying mechanism by which hypoxia-induced IL-32ß stability is regulated was investigated in ovarian cancer cells. IL-32ß expression increased under hypoxic conditions in ovarian cancer cells as it did in breast cancer cells. The amount of IL-32ß was regulated by post-translational control rather than by transcriptional activation. Under normoxic conditions, IL-32ß was continuously eliminated through ubiquitin-dependent degradation by the von-Hippel Lindau (VHL) E3 ligase complex. Oxygen deficiency or reactive oxygen species (ROS) disrupted the interaction between IL-32ß and VHL, leading to the accumulation of the cytokine. The fact that IL-32ß is regulated by the energy-consuming ubiquitination system implies that it plays an important role in oxidative stress. We found that IL-32ß reduced protein kinase Cδ (PKCδ)-induced apoptosis under oxidative stress. This implies that the hypoxia- and ROS-stabilized IL-32ß contributes to sustain survival against PKCδ-induced apoptosis.